Impact of single round of low dose CT lung cancer screening on cause of mortality in different socio-economic groups: a post-hoc analysis of long-term follow-up of the UKLS trial

Summary Background Lower socioeconomic status, as measured by the Index of Multiple Deprivation (IMD), is associated with higher rates of smoking-related disease mortality, and with poor uptake of cancer screening. Here we explore whether socioeconomic status impacts the effectiveness of a single round of low-dose-CT screening, or impacts other causes of death, in the UKLS LDCT screening trial. Methods IMD quintiles were defined according to UK-wide data, with the deprived group defined as the lower two quintiles (Q1-2) and the less deprived as Q3-5. Follow-up data was obtained for lung cancer diagnosis (median follow-up 9.1 years) and cause of death (median follow-up 9.9 years). Outcomes were compared based on IMD group and trial arm (CT or control). Findings More deprived quintiles were less likely to respond to the questionnaire, but this population was more likely to be selected for screening by the LLP risk model. Lower IMD quintiles benefitted from low-dose-CT screening in terms of lung cancer survival (HR 1.89, 95% CI 1.16–3.08) to the same extent as upper quintiles (HR 1.87, 95% CI 1.07–3.26). However, there was a bigger impact on deaths due to COPD and emphysema in more deprived quintiles. Interpretation Whilst LDCT screening benefit for lung cancer was similar, significant impact on the rates of death from other smoking-related diseases, notably COPD and emphysema, was seen primarily in lower socioeconomic groups. Future research is required to confirm how lung cancer screening benefits other disease outcomes. Funding 10.13039/501100000664NIHR Health Technology Assessment Programme; NIHR Policy Research programme; 10.13039/100009855Roy Castle Lung Cancer Foundation.


Impact of recruitment and risk selection on IMD profile and risk factor profiles
The UKLS target population consisted of two geographical areas with differing IMD profiles.Utilising the 75,948 UKLS questionnaire responders who provided adequate information both for IMD scoring and LLPv2 risk scores, we have examined the distribution of IMD quintiles.Notably the IMD profile of the total pool of respondents is skewed towards the upper quintiles, reflecting greater engagement and the higher proportion of respondents from the south (57%) which is more affluent.
As expected, compared to the total respondents, the IMD profile for the high-risk group is skewed toward the lower quintiles (chi-square P<0•001).Despite this the IMD profiles of the two trial participant groups (no CT and LDCT, representing 42.5% of the high-risk group) is less skewed than the total high-risk group, with a lower proportion of Q1 and a higher proportion of Q5, indicating that there is likely a further selective pressure against lower IMD groups for trial participation at this stage of section.Randomisation to LDCT was not biased by IMD (chi-square P = 0•91).

Relationship between individual LLP risk score variables and IMD in UKLS responders
Across the total 75,096 respondents with full risk factor data and IMD data, associations between lung cancer risk factors and lower IMD quintile were seen for all except history of pneumonia and personal history of cancer, both of which were more uniformly distributed (Table S1).
In the subgroup of 8,728 high-risk UKLS respondents (Table S2) only COPD, emphysema and family history of lung cancer were still significantly associated with lower IMD quintiles.History of asbestos exposure (previously associated with lower quintiles), pneumonia and personal history of cancer (both previously not associated with IMD) were associated with upper IMD quintiles.This represents the selection bias imposed by use of the LLP lung cancer risk score, when compared to the whole cohort, but may also be related to the greater proportion of upper quintile respondents (with generally lower smoking-related risk) for which these factors contributed significantly to their high-risk score.
In the 4,055 risk-selected trial participants (Table S3), only, COPD and family history of lung cancer were significantly associated with lower IMD quintiles, with some association for TB.History of pneumonia and personal history of cancer were both associated with upper IMD quintiles, as for the high-risk respondents in general, but asbestos exposure was no longer significant.Presumably there was some additional selection bias for those able and willing to take part in the LDCT screen, although the smaller sample size will reduce statistical significance.In the case of age, compared to all respondents (Figure S2A), age was higher in upper IMD quintiles in the highrisk group (Figure S2B).Whilst there was an even balance of gender in the total respondent group across all IMD quintiles (Figure S2C), the risk score significantly favours inclusions of males, but less so in the lowest quintile (Figure S2D).Greater smoking duration (Figure S2E & F) was clearly associated with lower IMD, with risk selection, as expected the higher smoking duration groups were selected, but the main difference between IMD quintiles was in the 40-60 year smoking group.1.
Relationship of IMD with LLP risk score, lung cancer incidence and mortality in the absence of LDCT screening Utilising the 75,096 UKLS responders, but excluding those 1994 participants that received LDCT, the 5-year incidence of lung cancer (Figure S4) follows the expected relationship with IMD in both the high-risk group (LLPv2 >4.5%) eligible for LDCT and the remaining low risk group.There appears to be selection bias in terms of lung cancer incidence, introduced when looking at UKLS participants (excluding those who received LDCT), with quintile 1 having a lower incidence than might be expected and quintile 5 a high incidence (Figure S5A).Notably Q2 initially had a greater incidence of lung cancer and higher mortality than Q1 and Q5 a greater incidence than either Q3 or Q4, although these differences are not statistically significant.The same is true for lung cancer mortality (Figure S5B).
Whilst differences in lung cancer risk factors may contribute towards the observed lung cancer incidence and outcome patterns between IMD quintiles, they were narrower within this age and risk-score selected cohort than in the general population.
A more useful analysis of lung cancer incidence and outcome can be achieved by grouping the lower two (Q1-2) and the upper three (Q3-5) IMD quintiles (Figure S6).
The number exposed at time points 0, 2, 4 and 6years (A) or 0, 2, 4, 6 and 8 years (B) are given, with the number of events in the subsequent time period (in brackets).

A B
Figure S6 Lung cancer incidence (A, log rank P < 0•001) and all-cause mortality (B, log rank P = 0•0045) in UKLS control cohort grouped as more deprived quintiles Q1-Q2 (blue) vs less deprived quintiles Q3-Q5 (red).The number exposed at time points 0, 2, 4 and 6years (A) or 0, 2, 4, 6 and 8 years (B) are given, with the number of events in the subsequent time period (in brackets).

Relationship of IMD with histological type
Looking at histological type distributions in different IMD quintiles, as expected there was a higher proportion of squamous cell carcinoma in the most deprived quintile (Q1 35.6%) than in other quintiles (Q2 11.5%, Q3 11.5%, Q4, 15.8%, Q5 16.7%, chi-square Q1 vs Q2-4 P= 0.005), potentially associated with greater smoking in the most deprived quintile, given squamous cell carcinoma has a greater association with smoking.
However, when looking at the quintile groups used for outcome analysis, whilst the proportion of squamous cell carcinoma was still higher in the more deprived group (Q1-2 29.3%) compared to the less deprived (Q3-5 14.7%), the distribution of histological type within these two IMD groups was not significantly different when looking at all histological types (chi-square P = 0.57) and only borderline when looking at the ratio of adenocarcinoma to squamous cell carcinoma (chi-square P = 0.041).
Similar patterns were seen in both arms of the trial, i.e. whether or not the subjects received LDCT.

Table S1
Categorical lung cancer risk factors and IMD in 75,096 UKLS respondents (red= high values, clear = middling values, blue = low values, scaled to range per variable) TableS2Categorical lung cancer risk factors and IMD in 8,728 high-risk UKLS respondents (colours as for TableS1)

Table S3
Categorical lung cancer risk factors and IMD in 4,055 UKLS trial subjects (colours as for TableS1)